Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Heel and toe clearance estimation for gait analysis using wireless inertial sensors.

Tripping is considered a major cause of fall in older people. Therefore, foot clearance (i.e., height of the foot above ground during swing phase) could be a key factor to better understand the complex relationship between gait and falls. This paper presents a new method to estimate clearance using a foot-worn and wireless inertial sensor system. The method relies on the computation of foot orientation and trajectory from sensors signal data fusion, combined with the temporal detection of toe-off and heel-strike events. Based on a kinematic model that automatically estimates sensor position relative to the foot, heel and toe trajectories are estimated. 2-D and 3-D models are presented with different solving approaches, and validated against an optical motion capture system on 12 healthy adults performing short walking trials at self-selected, slow, and fast speed. Parameters corresponding to local minimum and maximum of heel and toe clearance were extracted and showed accuracy ± precision of 4.1 ± 2.3 cm for maximal heel clearance and 1.3 ± 0.9 cm for minimal toe clearance compared to the reference. The system is lightweight, wireless, easy to wear and to use, and provide a new and useful tool for routine clinical assessment of gait outside a dedicated laboratory.

Glomerular filtration rate: measure creatinine and height rather than cystatin C!

AIM: Inulin clearance (Cin) is the gold standard for assessing glomerular filtration rate (GFR). Other methods are based on the plasma creatinine concentration (Pcreat), creatinine clearance (Ccreat), the Haycock-Schwartz formula and the plasma concentration of cystatin C (PcysC), a 13 kDa basic protein produced at a constant rate by all nucleated cells. The present prospective study was thus designed to evaluate the reliability of PcysC as a marker of GFR in comparison with that of Pcreat, Ccreat and the Haycock-Schwartz formula, using Cin as the gold standard. METHODS: Ninety-nine children (51 m/48 f), with a median age of 8.3 y (1.0-17.9) were studied. Using a cut-off for Cin of 100 ml/min per 1.73 m2, 54 children (54.5%) had impaired GFR. Those with normal GFR were comparable for age, height, weight and body mass index. RESULTS: Logistic regression, ROC analysis and linear regression all showed that Ccreat was the best parameter to discriminate between impaired and normal GFR, followed by the Haycock-Schwartz formula, PcysC, and finally Pcreat, each one being significantly more predictive than the next. CONCLUSION: GFR is better assessed by the Haycock-Schwartz formula than by PcysC or Pcreat alone. It is therefore concluded that when urine collection is not possible, simply measuring the child's Pcreat and height is the best, easiest and cheapest way to assess GFR.

Markedly reduced blood pressure responsiveness in endotoxemic rats; reversal by neuropeptide Y.

This study in conscious normotensive rats was performed to assess the effect of the vasoconstrictor peptide, neuropeptide Y (NPY), on blood pressure responsiveness to exogenous norepinephrine in endotoxaemia. NPY and endotoxin were infused at doses which had no effect on blood pressure, whether given alone or in combination. Endotoxin markedly reduced the pressor responses to bolus injections of norepinephrine. However, blood pressure responsiveness could be enhanced by infusing NPY simultaneously with the endotoxin. It is suggested that low dose NPY infusions may be clinically useful in reversing the reduced vascular responsiveness to pressor amines in shock.

Glomerular hyperfiltration and increased proximal sodium reabsorption in subjects with type 2 diabetes or impaired fasting glucose in a population of the African region.

BACKGROUND. Glomerular hyperfiltration (GHF) is a well-recognized early renal alteration in diabetic patients. As the prevalence of GHF is largely unknown in populations in the African region with respect to normal fasting glucose (NFG), impaired fasting glucose (IFG) and type 2 diabetes [diabetes mellitus (DM)], we conducted a cross-sectional study in the Seychelles islands among families including at least one member with hypertension. METHODS. The glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and proximal tubular sodium reabsorption were measured using inulin, p-aminohippurate (PAH) and endogenous lithium clearance, respectively. Twenty-four-hour urine was collected on the preceding day. RESULTS. Of the 363 participants (mean age 44.7 years), 6.6% had IFG, 9.9% had DM and 63.3% had hypertension. The prevalence of GHF, defined as a GFR >140 ml/min, was 17.2%, 29.2% and 52.8% in NFG, IFG and DM, respectively (P trend <0.001). Compared to NFG, the adjusted odds ratio for GHF was 1.99 [95% confidence interval (CI) 0.73-5.44] for IFG and 5.88 (2.39-14.45) for DM. Lithium clearance and fractional excretion of lithium were lower in DM and IFG than NFG (P < 0.001). CONCLUSION. In this population of African descent, subjects with impaired fasting glucose or type 2 diabetes had a high prevalence of GHF and enhanced proximal sodium reabsorption. These findings provide further insight on the elevated incidence of nephropathy reported among African diabetic individuals.

Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers.

While it was thought that most of cerebral creatine is of peripheral origin, AGAT and GAMT are well expressed in CNS where brain cells synthesize creatine. While the creatine transporter SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), it is absent from their surrounding astrocytes. This raised the concept that BBB has a limited permeability for peripheral creatine, and that the brain supplies a part of its creatine by endogenous synthesis. This review brings together the latest data on creatine and guanidinoacetate transport through BBB and blood-CSF barrier (BCSFB) with the clinical evidence of AGAT-, GAMT- and SLC6A8-deficient patients, in order to delineate a clearer view on the roles of BBB and BCSFB in the transport of creatine and guanidinoacetate between periphery and CNS, and on brain synthesis and transport of creatine. It shows that in physiological conditions, creatine is taken up by CNS from periphery through SLC6A8 at BBB, but in limited amounts, and that CNS also needs its own creatine synthesis. No uptake of guanidinoacetate from periphery occurs at BBB except under GAMT deficiency, but a net exit of guanidinoacetate seems to occur from CSF to blood at BCSFB, predominantly through the taurine transporter TauT.

Biokinetics and dosimetry of (111)In-DOTA-NOC-ATE compared with (111)In-DTPA-octreotide.

PURPOSE: The biokinetics and dosimetry of (111)In-DOTA-NOC-ATE (NOCATE), a high-affinity ligand of SSTR-2 and SSTR-5, and (111)In-DTPA-octreotide (Octreoscan?, OCTREO) were compared in the same patients. METHODS: Seventeen patients (10 men, 7 women; mean age 60 years), referred for an OCTREO scan for imaging of a neuroendocrine tumour (15), thymoma (1) or medullary thyroid carcinoma (1), agreed to undergo a second study with NOCATE. Whole-body anterior-posterior scans were recorded 0.5 (100 % reference scan), 4, 24 and 48 h (17 patients) and 120 h (5 patients) after injection. In 16 patients the OCTREO scan (178 ± 15 MBq) was performed 16 ± 5 days before the NOCATE scan (108 ± 14 MBq) with identical timing; 1 patient had the NOCATE scan before the OCTREO scan. Blood samples were obtained from 14 patients 5 min to 48 h after injection. Activities expressed as percent of the initial (reference) activity in the whole body, lung, kidney, liver, spleen and blood were fitted to biexponential or single exponential functions. Dosimetry was performed using OLINDA/EXM. RESULTS: Initial whole-body, lung and kidney activities were similar, but retention of NOCATE was higher than that of OCTREO. Liver and spleen uptakes of NOCATE were higher from the start (p < 0.001) and remained so over time. Whole-body activity showed similar α and β half-lives, but the β fraction of NOCATE was double that of OCTREO. Blood T (1/2)β for NOCATE was longer (19 vs. 6 h). As a result, the effective dose of NOCATE (105 μSv/MBq) exceeded that of OCTREO (52 μSv/MBq), and the latter result was similar to the ICRP 106 value of 54 μSv/MBq. Differential activity measurement in blood cells and plasma showed an average of <5 % of NOCATE and OCTREO attached to globular blood components. CONCLUSION: NOCATE showed a slower clearance from normal tissues and its effective dose was roughly double that of OCTREO.

Acetaminophen increases blood pressure in patients with coronary artery disease.

BACKGROUND: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. METHODS AND RESULTS: The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. CONCLUSIONS: This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Formule sanguine: intérêt des nouveaux paramètres [Complete blood counts: new parameters].

Performing a complete blood count analysis is a daily routine necessary for a good care of patients. Nowadays, modern blood analyzers provide on top of classical blood values, several additional parameters. In this paper, using short case presentations, we discuss how to interpret these results and integrate them in the clinical context.

No use for waist-for-height ratio in addition to body mass index to identify children with elevated blood pressure.

Abstract Background. In children, waist-for-height ratio (WHtR) has been proposed to identify subjects at higher risk of cardiovascular diseases. The utility of WHtR to identify children with elevated blood pressure (BP) is unclear. Design. Cross-sectional population-based study of schoolchildren. Methods. Weight, height, waist circumference and BP were measured in all sixth-grade schoolchildren of the canton de Vaud (Switzerland) in 2005/06. WHtR was computed as waist [cm]/height [cm]. Elevated BP was defined according to sex-, age- and height-specific US reference data. The area under the receiver operating characteristic curve (AUC) statistic was computed to compare the ability of body mass index (BMI) z-score and WHtR, alone or in combination, to identify children with elevated BP. Results. 5207 children participated (76% response) [2621 boys, 2586 girls; mean (± SD) age, 12.3 ± 0.5 years; range: 10.1-14.9]. The prevalence of elevated BP was 11%. Mean WHtR was 0.44 ± 0.05 (range: 0.29- 0.77) and 11% had high WHtR (> 0.5). BMI z-score and WHtR were strongly correlated (Spearman correlation coefficient r = 0.76). Both indices were positively associated with elevated BP. AUCs for elevated BP was relatively low for BMI z-score (0.62) or for WHtR (0.62), and was not substantially improved when both indices were considered together (0.63). Conclusions. The ability of BMI z-score or WHtR to identify children aged 10-14 with elevated BP was weak. Adding WHtR did not confer additional discriminative power to BMI alone. These findings do not support the measurement of WHtR in addition to BMI to identify children with elevated BP.

Aortic vessel wall magnetic resonance imaging at 3.0 Tesla: a reproducibility study of respiratory navigator gated free-breathing 3D black blood magnetic resonance imaging.

The purpose of this study was to evaluate a free-breathing three-dimensional (3D) dual inversion-recovery (DIR) segmented k-space gradient-echo (turbo field echo [TFE]) imaging sequence at 3T for the quantification of aortic vessel wall dimensions. The effect of respiratory motion suppression on image quality was tested. Furthermore, the reproducibility of the aortic vessel wall measurements was investigated. Seven healthy subjects underwent 3D DIR TFE imaging of the aortic vessel wall with and without respiratory navigator. Subsequently, this sequence with respiratory navigator was performed twice in 10 healthy subjects to test its reproducibility. The signal-to-noise (SNR), contrast-to-noise ratio (CNR), vessel wall sharpness, and vessel wall volume (VWV) were assessed. Data were compared using the paired t-test, and the reproducibility of VWV measurements was evaluated using intraclass correlation coefficients (ICCs). SNR, CNR, and vessel wall sharpness were superior in scans performed with respiratory navigator compared to scans performed without. The ICCs concerning intraobserver, interobserver, and interscan reproducibility were excellent (0.99, 0.94, and 0.95, respectively). In conclusion, respiratory motion suppression substantially improves image quality of 3D DIR TFE imaging of the aortic vessel wall at 3T. Furthermore, this optimized technique with respiratory motion suppression enables assessment of aortic vessel wall dimensions with high reproducibility.

Disposition of oral valganciclovir during continuous renal replacement therapy in two lung transplant recipients

Background: Oral valganciclovir (VGC) is hydrolysed into active ganciclovir (GCV) which is eliminated in the kidney by filtration and secretion. VGC dosage has to be adapted in renal failure with continuous renal replacement therapy (CRRT), a condition sometimes encountered early after solid organ transplantation. This investigation aimed to determine whether VGC 450 mg every 48 hours provides appropriate GCV exposure for cytomegalovirus (CMV) prophylaxis during CRRT. Methods: GCV pharmacokinetics were extensively studied during CRRT in two lung transplant recipients with acute renal failure receiving VGC 450 mg every 48 hours trough a nasogastric tube. In vitro experiments using blank whole blood spiked with GCV further investigated exchanges between plasma and erythrocytes. Results: GCV disposition was characterised by an area under the curve (AUC) of 98.0 and 55.4 mg h/L, resulting in trough concentrations of 0.7 and 0.2 mg/L, an apparent total body clearance of 3.3 and 5.8 L/h, a terminal half-life of 16.9 and 14.1 h, and an apparent volume of distribution of 60.3 and 104.9 L. The observed sieving coefficient (filtrate/plasma) was 1.05 and 0.96, and the hemofiltration clearance 3.3 and 3.1 L/h, respectively. High sieving values could be explained by an efflux of GCV from erythrocytes. In vitro experiments confirmed that erythrocytes are loaded with significant GCV amount and release it quickly into plasma, thus contributing to the apparent efficacy of hemofiltration. Conclusion: These results indicate that a VGC dosage of 450 mg every 48 hours was adequate for CMV prophylaxis during CRRT, providing GCV levels similar to those reported using 900 mg qd in transplant recipients with normal renal function.

Risk of cardiovascular events and blood pressure control in hypertensive HIV-infected patients: Swiss HIV Cohort Study (SHCS).

BACKGROUND: Prevalence of hypertension in HIV infection is high, and information on blood pressure control in HIV-infected individuals is insufficient. We modeled blood pressure over time and the risk of cardiovascular events in hypertensive HIV-infected individuals. METHODS: All patients from the Swiss HIV Cohort Study with confirmed hypertension (systolic or diastolic blood pressure above 139 or 89 mm Hg on 2 consecutive visits and presence of at least 1 additional cardiovascular risk factor) between April 1, 2000 and March 31, 2011 were included. Patients with previous cardiovascular events, already on antihypertensive drugs, and pregnant women were excluded. Change in blood pressure over time was modeled using linear mixed models with repeated measurement. RESULTS: Hypertension was diagnosed in 2595 of 10,361 eligible patients. Of those, 869 initiated antihypertensive treatment. For patients treated for hypertension, we found a mean (95% confidence interval) decrease in systolic and diastolic blood pressure of -0.82 (-1.06 to -0.58) mm Hg and -0.89 (-1.05 to -0.73) mm Hg/yr, respectively. Factors associated with a decline in systolic blood pressure were baseline blood pressure, presence of chronic kidney disease, cardiovascular events, and the typical risk factors for cardiovascular disease. In patients with hypertension, increase in systolic blood pressure [(hazard ratio 1.18 (1.06 to 1.32) per 10 mm Hg increase], total cholesterol, smoking, age, and cumulative exposure to protease inhibitor-based and triple nucleoside regimens were associated with cardiovascular events. CONCLUSIONS: Insufficient control of hypertension was associated with increased risk of cardiovascular events indicating the need for improved management of hypertension in HIV-infected individuals.

Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many cells and tissues including pancreatic beta-cells, liver, skeletal muscle, and adipocytes. This study investigates the potential role of MIF in carbohydrate homeostasis in a physiological setting outside of severe inflammation, utilizing Mif knockout (MIF-/-) mice. Compared with wild-type (WT) mice, MIF-/- mice had a lower body weight, from birth until 4 months of age, but subsequently gained weight faster, resulting in a higher body weight at 12 months of age. The lower weight in young mice was related to a higher energy expenditure, and the higher weight in older mice was related to an increased food intake and a higher fat mass. Fasting blood insulin level was higher in MIF-/- mice compared with WT mice at any age. After i.p. glucose injection, the elevation of blood insulin level was higher in MIF-/- mice compared with WT mice, at 2 months of age, but was lower in 12-month-old MIF-/- mice. As a result, the glucose clearance during intraperitoneal glucose tolerance tests was higher in MIF-/- mice compared with WT mice until 4 months of age, and was lower in 12-month-old MIF-/- mice. Insulin resistance was estimated (euglycemic-hyperinsulinemic clamp tests), and the phosphorylation activity of AKT was similar in MIF-/- mice and WT mice. In conclusion, this mouse model provides evidence for the role of MIF in the control of glucose homeostasis.